The present invention relates to hydrochlorides of vancomycin antibiotics and to process for producing the same.
Vancomycin antibiotics are amphoteric and strongly levorotatory glycopeptide antibiotics having relatively high molecular weight [Williams et. al., Topics in Antibiotic Chemistry, 5, 119-158 (1980)]. Examples of the known vancomycin antibiotics are vancomycin, ristocetin, actinoidin, teichomycin A2, LL-AM-374, A477, OA7653 and A35512B. Vancomycin has been made into pharmaceutical preparations in a form of its hydrochloride for the therapy of infectious diseases, especially for the therapy of infectious diseases caused by Staphylococcus and by methicillin-resistant strains and has been supplied for oral and parenteral uses as a dried solid preparation filled in aseptic vials or small bottles. It is also useful as a substance for improving the utilizing rate of feed for ruminants.
For example, a dried solid of vancomycin hydrochloride is prepared by a freeze-drying of an aqueous solution of vancomycin hydrochloride but there is a disadvantage that, when the freeze-drying is finished, the said dried solid of vancomycin hydrochloride is hardly disintegrated and shows a poor filling property. In order to overcome such a disadvantage, a producing method which is characterized in conducting a freeze-drying prom a solution containing an organic solvent such as alcohol has been known (cf. U.S. Pat. No. 4,885,275) but there is a possibility that the organic solvent remains in the dried solid.
The present invention is to provide process for producing of hydrochlorides of vancomycin antibiotics which can be easily disintegrated and has excellent filling property from an aqueous solution of hydrochlorides of vancomycin antibiotics.
In accordance with the present invention, there is provided process for producing hydrochlorides of vancomycin antibiotics, characterized in that an aqueous solution of hydrochlorides of vancomycin antibiotics is subjected to a primary freezing at from xe2x88x921xc2x0 C. to xe2x88x9220xc2x0 C. and then subjected to a secondary freezing at from xe2x88x9225xc2x0 C. to xe2x88x9280xc2x0 C., and the resulting frozen solid is dried in vacuo.
As hereunder, the process of the present invention is more specifically illustrated taking vancomycin hydrochloride as an example of hydrochlorides of vancomycin antibiotics.
Vancomycin is added to water (preferably water for injection) and is dissolved by adding hydrochloric acid (preferably 6N hydrochloric acid) with stirring and the solution is adjusted to pH 3.4-3.6 (preferably 3.45-3.50). Additional water (preferably water for injection) is added to prepare a vancomycin hydrochloride solution where the concentration of vancomycin is 10-20% (preferably 13-17%). Then this is subjected to an activated carbon treatment and/or filtration treatment through an aseptic filter if necessary and, after that, the said solution is filled in a container for freeze-drying (such as a tray made of stainless steel or vial, etc.; preferably a tray made of stainless steel). Although thickness of the liquid is not particularly limited, the thickness of the liquid of 1-30 mm is preferred and the particularly preferred thickness of the liquid is 11-14 mm.
The vancomycin hydrochloride solution is subjected to a primary freezing at from xe2x88x921 to xe2x88x9220xc2x0 C. (preferably from xe2x88x923xc2x0 C. to xe2x88x925xc2x0 C.) as temperature of the container for freeze-drying until ice crystals grow in an entire solution. At that time, in order to make the formation of ice crystals easy, it is also possible that a quick cooling is firstly conducted down to about xe2x88x9220xc2x0 C. to form ice crystals and then the primary freezing is carried out at the above-mentioned temperature. The resulting primarily frozen substance is subjected to a secondary freezing at from xe2x88x9225xc2x0 C. to xe2x88x9280xc2x0 C. (preferably from xe2x88x9235xc2x0 C. to xe2x88x9245xc2x0 C.) until it is completely frozen and solidified.
Drying of the resulting secondarily frozen substance may be carried out by means of drying in vacuo under warming in accordance with the conventional method for freeze-drying. Each of the above steps may be carried out under an aseptic condition if necessary.
Vancomycin which is used in the present invention is manufactured by multi-staged steps of purification and isolation from a fermentation broth prepared by fermentation of, for example, Streptomyces orientalis (cf. U.S. Pat. No. 3,067,099, etc.). Generally, the fermentation broth is filtered to remove solids and mycelia and purified using various kinds of adsorbent resin, etc., and the product is manufactured from the resulting concentrated solution by means of crystallization or freeze-drying. Purification may be carried out by a purifying method using a porous nonionic styrene-divinylbenzene copolymer as a resin (cf. U.S. Pat. No. 4,440,753); a purifying method using a peptide-immobilized ligand matrix (cf. U.S. Pat. No. 4,778,846 and U.S. Pat. No. 4,667,024); a purifying method where vancomycin is adsorbed with alumina and developed and eluted using an aqueous solution of hydrochloric acid containing an organic solvent such as methanol; a purifying method where vancomycin is adsorbed with an ion-exchange resin in which a carboxymethyl group is introduced into synthetic polymer gel having a hydrophilic hydroxyl group (such as a substance using polyvinyl gel as a synthetic polymer gel) and eluted with an aqueous solution of ammonium chloride, etc.; and the like. If necessary, two or more purifying methods may be combined.